This paper explores the utility of expanding the harm reduction paradigm to incorporate vulnerability reduction. The thrust of harm reduction interventions to date, particularly in injection drug use, has been risk reduction. Many interventions have been designed to reduce drug-related harm by altering high-risk behaviours. Vulnerability looks behind risk. The notion of vulnerability incorporates the complex of underlying factors that promotes harmful outcomes as a result of drug use, and limits attempts to modify drug use to make harmful outcomes less likely. A conceptual framework will be introduced that looks at harm, risk and vulnerability at the three levels of individual, community and society. This paper uses illicit injection drug use as an example. This conceptual framework will be used to position human rights more centrally in the harm reduction debate. Human rights violations and infringements can contribute to drug-related harm by first creating the preconditions for risky drug use; and second, by limiting access to prevention and care. A human rights framework allows us to better understand vulnerability to drug-related harm, and provides an important advocacy tool for improved interventions. This expanded harm reduction paradigm that incorporates vulnerability and human rights allows for better development of a public health approach in harm reduction, exposes gaps in research, and allows for better development of more effective interventions.